ES2574210T3 - Methods and compositions to treat or prevent the symptoms of hormonal variations - Google Patents

Abstract

Dextromethorphan or dextrorphan, or a pharmaceutically acceptable salt of any of these, for use in a method for treating or preventing symptoms of hormonal variation; said method comprises identifying a subject having one or more symptoms of hormonal variations selected from hot flashes and night sweats and administering an effective amount of said dextromethorphan or dextrorphan or salt to the subject.

Description

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Methods and compositions for treating or preventing the symptoms of hormonal variations Field of the invention

The present description describes methods, compositions, and cases for the treatment or prevention of the symptoms of hormonal variation associated with menopause, surgery, anti-estrogen drugs and / or androgen deprivation therapy, such as hot flashes, night sweats, and insomnia.

Background of the invention

Hot flashes are the most common symptoms experienced by perimenopausal or postmenopausal women and also appear in men with prostate cancer who undergo androgen deprivation therapy (ADT). Generally, hot flashes are systematic and are probably the result of an alteration in the thermoregulatory center of the set point, which is located in the preoptic anterior hypothalamus, with the participation of dopamine, serotonin, norepinephrine, and alpha-adrenergic receptors.

Symptoms of hot flashes include a sudden sensation of heat, usually accompanied by reddening of the skin, perspiration, palpitations, anxiety, irritability, and even panic and night sweats. These can be characterized by light heat until profuse sweating. Typical hot flashes occur with the sudden appearance of a sensation of heat in the chest, which then extends upward to involve the neck and face. Other people feel a sudden appearance of heat throughout the upper body. After a hot flash, cold may occur due to a subsequent decrease in core temperature. Hot flashes can also be accompanied by dizziness, nausea, headaches, palpitations, and profuse sweating. These symptoms can disrupt sleep and work and interfere with the quality of life.

The severity of suffocation sensations varies greatly from one to another in the same person and from person to person. Hot flashes have been studied in perimenopausal and postmenopausal women but have not been studied extensively in men. Hot flashes in a woman can occur several times in a week up to as often as once per hour. Each episode can last from a few seconds to sixty minutes, depending on the woman. Hot flashes are caused by several factors such as hot weather, stress, food intake, or alcohol consumption. The severity and duration of hot flashes can result in sleep deprivation and interference with work and lifestyle.

Perimenopausal and postmenopausal women are prone to hot flashes. In fact, almost 60-70% of postmenopausal women have hot flashes, and approximately 10-20% of all postmenopausal women will report intolerable symptoms. Some women may have these symptoms for up to 15 years. Therefore, the identification and proper control of menopausal and postmenopausal symptoms are crucial to maintaining a woman's quality of life.

Hot flashes are also a common and potentially chronic problem in men. For example, men with prostate cancer who undergo aDt may have hot flashes. This is a major problem for the quality of life of a significant proportion of men receiving ADT. A report shows that the natural history of hot flashes in men, which includes the variation of severity and frequency, has not been studied extensively. It is known that almost 70% of men who undergo surgical orchiectomy report hot flashes. Approximately 70 to 80% of men with long-term androgen suppression have hot flashes, and 30 to 40% of these patients report that symptoms are an important source of discomfort.

Although the pathophysiology of hot flashes is not fully known, it has been postulated that hot flashes are the result of a transient decrease in the hypothalamic temperature regulation setpoint. Due to the temporal relationship between changes in sex hormone concentrations and the appearance of hot flashes, it is believed that these symptoms are the result of decreased estrogen levels or increased gonadotropin concentrations. Therefore, hot flashes occur commonly in menopausal women, but they also occur in premenopausal women who take antiestrogen drugs, such as tamoxifen. The administration of aromatase inhibitors, which are anti-estrogen drugs administered to menopausal women with a history of breast cancer, can also result in hot flashes as a side effect. Men with androgen deprivation treatment may also experience such symptoms.

Although estrogen replacement therapy can effectively minimize or prevent hot flashes in women, many women are concerned about the potential risks of hormone replacement therapy. This is especially true for women who suffer from breast cancer or who have a family history of breast cancer, and / or a history of bleeding disorders.

Several non-hormonal agents have been tested for the treatment of hot flashes symptoms. One of

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These agents are clonidine, an agonist of the quadratura.sub.2 centrally acting adrenergic receptors. In the brain it selectively stimulates the receptors that control the levels of catecholamine in the blood. These receptors close a negative feedback loop that begins with the sympathetic nerves descending from the brain that control the production of catecholamines (for example, epinephrine, also known as adrenaline, and norepinephrine) in the adrenal medulla. Clonidine deceives the brain by believing that the levels of catecholamines are higher than they really are, which causes the brain to reduce its signals to the adrenal medulla, and leads to a decrease in the production of catecholamines. The result is a decrease in heart rate and blood pressure. In randomized clinical trials, clonidine proved to be moderately more effective than placebo, but adverse effects are common, and include dry mouth, dizziness, and blurred vision.

Recent randomized clinical trials have also confirmed that some selective serotonin reuptake inhibitors (SSRIs), such as venlafaxine and paroxetine, are more effective than placebo in minimizing the incidence and severity of hot flashes. However, the adverse effects with SSRI are moderate, and include headache, agitation, tremor, sedation, and sexual dysfunction.

There are also a series of treatments for hot flashes that seem to have similar effects in men and women. The decrease in the frequency of hot flashes in women treated with clonidine is approximately IQ-15 percent higher than that seen with placebo. In a double-blind, cross-clonidine study to reduce the frequency of self-reported hot flashes in men, a similar effect was observed, but the difference in placebo effect was not statistically significant. Research has found practically identical results for men and women receiving megestrol acetate for hot flashes, with a reduction of approximately 8Q% in the frequency of self-reported hot flashes compared to a 2Q% reduction with placebo. However, higher levels of vaginal bleeding were also associated with the use of megestrol acetate in women.

Many women look for complementary and alternative medicine (CAM) methods to relieve their menopausal symptoms. Compounds used as complementary and alternative medicine include Soy Vitamin E, red clover (Trifolium pratense), dong quai, evening primrose oil, and black cohosh (Cimicifuga racemosa).

In recent years, anecdotal reports suggest that the antidepressants of the SSRI / SNRI groups could reduce the symptoms of hot flashes. These observations led to initial pilot studies and then to randomized controlled clinical trials with placebo. In pilot studies, venlafaxine sNrI (Effexor) and SSRI paroxetine (Paxil) were associated with hot flashes punctuation in the order of 55% -75%. Other pilot evaluations have suggested that citalopram (Celexa) and mirtazapine (Remeron) also relieve hot flashes to a similar degree. The first randomized clinical trial of one of these new antidepressants compared three doses of venlafaxine (37.5, 75, and 15Q mg / dfa) with placebo. While low-dose venlafaxine was only slightly more effective than placebo (37% reduction vs. 27% in hot flashes scores, respectively), both moderate and high doses were associated with a statistically significant reduction of 61%. in hot flashes scores. Fluoxetine (Prozac) at 2Q mg / day was associated with a 5Q% reduction in hot flush scores compared to a 36% reduction with placebo.

More recently, anecdotal observations suggesting efficacy led to trials to evaluate the value of another compound, gabapentin (Neurontin ™). Gabapentin is a gamma-aminobutyric acid (GABA) analog that has been prescribed most frequently for the treatment of seizures and neuropathic pain. It is also effective in other syndromes, such as panic disorder, social phobia, migraine headache, and essential tremor. Based on anecdotal observations, pilot and randomized trials of gabapentin for the treatment of hot flashes were launched. The results of the pilot trials suggest that gabapentin reduces the incidence of hot flashes by 42% -7Q%. The benefit was demonstrated regardless of the simultaneous use of a stable dose of an SSRI / SNRI agent.

Serada ™, another formulation of gabapentin, was also tested in clinical trials for the treatment of menopausal hot flashes. Serada ™ dosed once a day (12Qq mg) or twice a day (6Qq mg in the morning and 12QQ mg at night for a total of 18QQ mg) resulted in a significant reduction in the frequency and severity of the hot flashes measured after four weeks. However, this effect was not found after 12 weeks of use.

Given the risks of estrogen replacement therapy and the marginal benefits of current non-hormonal treatments, there is a continuing need for alternative methods or compositions such as drugs to treat or prevent symptoms associated with menopause, surgery, anti-estrogen drugs. , and / or androgen deprivation therapy, including hot flashes. Alternative methods and compositions are described herein that avoid the dangers of estrogen replacement therapy while providing effective treatment of symptoms.

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Summary of the invention

In the present description methods and compositions for the treatment and prevention of the symptoms of hormonal variation are described. Specifically, the present description relates to the treatment and prevention of symptoms associated with menopause, surgery, anti-estrogen drugs, and / or androgen deprivation therapy, such as hot flashes, night sweats, and insomnia, which frequently both males and females experience.

In one aspect, the invention relates to dextromethorphan or dextrorphan, or a pharmaceutically acceptable salt of any of these, for use in a method for the treatment or prevention of the symptoms of hormonal variation; said method comprises identifying a subject that has one or more symptoms of hormonal variations selected from hot flashes and night sweats and administering an effective amount of said dextromethorphan or dextrorphane or salt to the subject.

In a second aspect, the invention relates to dextromethorphan or dextrorphan, or a pharmaceutically acceptable salt of any of these, in combination with another compound known to reduce or prevent the symptoms of hormonal variation, for use in a method for treatment or the prevention of the symptoms of hormonal variation selected from hot flashes and night sweats; said method comprises identifying a subject that has one or more symptoms of hormonal variations and administering an effective amount of said dextromethorphan or dextrorphan or salt and said other compound to the subject.

In a third aspect, the invention is directed to the use of dextromethorphan or dextrorphan, or a pharmaceutically acceptable salt of any of these, in the manufacture of a pharmaceutical composition for the treatment or prevention of the symptoms of hormonal variation selected from hot flashes and night sweats, wherein said dextromethorphan or dextrorphan or salt is present in said pharmaceutical composition in an effective amount in a pharmaceutically acceptable carrier.

In this description, cases are also described for carrying out a method described in the present description. Typically, the kits described in the present description comprise a receptor antagonist for treating or preventing the symptoms of hormonal variation and instructions for a method described in the present description. The kits may also comprise some or all of the other reagents and supplies necessary to perform at least one aspect of a method described in the present description.

These and other advantages and features that characterize the invention are set forth in the claims attached to the present description and form an additional part thereof. However, for a better understanding of the invention, and the advantages and objectives achieved through its use, reference should be made to the accompanying descriptive subject, in which illustrative embodiments of the invention are described.

Detailed description of the invention

Methods, compositions, and cases for treating or preventing symptoms associated with hormonal variations are described herein, particularly those associated with hormonal changes that accompany menopause, surgery, anti-estrogen drugs and / or deprivation therapy. of androgens. The present description relates to specific subtypes of dopamine, serotonin, and adrenergic receptors as effective targets for the treatment of hot flashes and other symptoms associated with hormonal variations. Specifically, the inventor has surprisingly discovered that receptor antagonists of the type that bind at least one of a serotonin receptor of type 2A (5-HT.sub.2A) and / or a dopamine receptor of type 2 (D .sub.2), commonly used as cough suppressant drugs (cough suppressants), can be used to treat or prevent symptoms associated with hormonal variations.

Accordingly, in one aspect of the present description methods are described for treating or preventing the symptoms of hormonal variation, particularly associated with perimenopause, menopause, surgery, anti-estrogen drugs, and / or androgen deprivation therapy. The methods include identifying a subject that has one or more symptoms of hormonal variations, and administering to the subject an effective amount of a compound described in the present description.

It has been found that specific subtypes of dopamine, serotonin and adrenergic receptors are effective targets for the treatment of hot flashes and other symptoms associated with hormonal variations. Serotonin-like receptors that are effective targets have been found to include 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A, 5-HT6, and 5-HT7. Dopamine-like receptors that are effective targets have been found to include D1, D2, D3, D4 and D5. Although previous specific receptors have been discussed, The present description is also applicable to other serotonin and dopamine receptors that interact with the receptor antagonists described in the present description.

Receptor antagonists that interact with the receptors discussed above and have been found to be effective in reducing or eliminating symptoms associated with hormonal variations include the

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5-HT.sub.2A antagonists and / or dopamine D.sub.2 antagonists. Such 5-HT.sub.2A antagonists include amantadine, ibogama, ketamine, memantine, riluzole, aptiganel, dizocipline, HU-211 , remacemide, ketobemidone, methadone, tramadol, aripiprazole, asenapine, clozapine, cyproheptadine, eplivanserine, etoperidone, iloperidone, ketanserine, methysergide, mianserin, mirtazapine, nefazodone, olanzapina, pinazantin, pinazathidine, pinazathidine, travanedine, pinazantinone, travanedone, travanedone Dopamine D.sub.2 antagonists include melperone, risperidone, ziprasidone and raclopride. Other receptor antagonists that have the functional characteristics of interacting with serotonin and / or dopamine type receptors are also contemplated as part of the present description.

In the present invention, the compound used is dextromethorphan or dextrorphan, or a pharmaceutical salt of any of these, preferably, dextromethorphan HBr. Dextromethorphan is the dextrogiro enantiomer of the metallic ether of levorphanol, an opioid analgesic. Dextromethorphan is rapidly absorbed in the gastrointestinal tract, where it enters the bloodstream and crosses the blood-brain barrier. It is known that dextromethorphan is a serotonin transport blocker and a norepinephrine transport blocker. After absorption in the gastrointestinal tract, CYP2D6, an enzyme of cytochrome P450, converts dextromethorphan into the active metabolite dextrorphan in the liver. Dextrorphan is an active metabolite of dextromethorphan and the therapeutic activity of dextromethorphan is considered to be caused by both the drug and this metabolite.

Dextromethorphan HBr is a specific form of dextromethorphan. HBr, i.e. bromohydrate, refers to bromfndric acid that is used primarily for the production of inorganic bromides, especially zinc, calcium, and sodium bromides. While HBr dextromethorphan is referred to as a specific form of dextromethorphan used in the invention, it will be apparent to those skilled in the art that other forms may be used.

The methods described in the present description can be used in male or female subjects. It is anticipated that the methods will be used for subjects who are likely to have, who currently have, or who are expected to have symptoms of hormonal variation. These include subjects who are in perimenopause, menopause, who wait for, or who have undergone surgery, androgen deprivation therapy or chemotherapy, subjects who are given goserelin (such as Zoladex ™) or leuprolide (such as Lupron ™) to induce menopause, subjects who consume antiestrogen drugs (such as tamoxifen or aromatase inhibitors), and / or any other condition that results in changes in hormonal levels.

Symptoms of hormonal variation include a sudden sensation of heat, usually accompanied by reddening of the skin, sweating, palpitations, anxiety, irritability, and even panic and night sweats. After a hot flash, fno may occur due to a subsequent decrease in core temperature. Hot flashes can also be accompanied by dizziness, nausea, headaches, palpitations, and profuse sweating. Although any of these symptoms can be relieved or prevented with the methods described in the present description, the methods are expected to reduce or prevent hot flashes, which will result in a reduction, elimination, or prevention of the symptoms caused by hot flashes.

Among the aspects described in the present description, a method for treating or preventing the symptoms of hormonal variations may comprise the use of an effective amount of a compound described in the present description. An effective amount will depend on the mode of administration, the frequency of administration, and the type of pharmaceutical composition used to deliver the compound to a patient, as well as the weight, gender, age, and physical conditions of the patient.

Generally, the effective amounts of said compounds will be about 0.002 mg to about 1.0 mg / kg body weight per day, preferably about 0.005 mg to 1.0 mg / kg body weight per day and more preferably about 0.005 to about 0.7 mg / kg body weight per day. For example, daily doses may be in the range of about 0.1 to about 50 mg per day for an adult patient weighing about 50 kg (110 lb), or about 0.2 to about 100 mg per day for a adult patient weighing approximately 100 kg (220 lb). In a preferred embodiment, about 30 to about 45 mg per day of dextromethorphan, dextromethorphan HBr or dextrorphan is administered to a subject. It is expected that no more than 120 mg of a daily dose be administered. Typically, the maximum daily dose needed in the majority of cases will be 100 mg for the methods described in the present description. Although the individual needs go, the determination of the optimum range of the effective amounts of each compound is within the skill of a person skilled in the art. By treating the symptoms of hormonal variations, which include hot flashes, the number (incidence or frequency), duration, and / or severity of symptomatic events can be reduced.

The administration of an effective amount of a compound described herein to a patient may be by any suitable route used to administer similar pharmaceutical products to a patient, including oral administration (such as a solution, gel, tablet, capsule, and powder), injection, suppository, infusible, pill, cream, ointment, inhalant, transdermal patch, and the like. The compound can be administered with any substance that is biologically tolerable (ie, non-toxic or present in an amount that is not toxic). Examples of such substances are well known to those skilled in the art and

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include, without limitation, sugars, salts, acids, drugs, excipients, carriers, flavorings, fillers, binders, gums, dyes, water, buffers, detergents, biologically active compounds, and the like.

The administration of an effective amount of a compound described herein to a subject may be in a dose or the method may comprise two or more administrations of less than the effective amount, where the amount ultimately administered is an effective amount. For example, if 30 mg is administered per day, a dose of 30 mg may be provided, two doses of 15 mg may be provided, three doses of 10 mg may be provided in one day, etc. Likewise, multiple administrations of an effective dose may be convenient where the second or subsequent administration is performed at a time well separated from the first administration. In addition, it may be desired to administer the effective dose with the use of a slow release method (also called sustained release, or prolonged) instead of immediate release. In this case, the total effective amount is administered but the compound is systematically released into the subject for hours instead of minutes.

The effective amount to be administered of a compound described in the present description to a subject may be less if one or more other compounds that reduce the symptoms of hormonal variation are administered simultaneously to the subject. These compounds include, but are not limited to, compounds used as complementary and alternative medicine such as soy vitamin E, red clover (Trifolium pratense), dong quai, evening primrose oil, and black cohosh (Cimicifuga racemosa). These compounds may also include drugs considered conventional that include, but are not limited to, conjugated estrogens (ie, a type of hormone replacement therapy, that is, "HRT", such as Cenestin ™, Enjuvia ™, and Premarin ™ ), bupropian (such as Wellbutrin ™, Zyban ™, Aplenzin ™, and Budeprion ™), venlafaxine (such as Effexor ™), fluoxetine (such as Prozac ™, Rapiflux ™, and Sarafen ™), duloxetine (such as Cymbalta ™) , sertraline (such as Zoloft ™), clonidine (such as Catapres-TTS-1 ™, Catapres-TTS-2 ™, and Catapres-TTS-3 ™), clonidine hydrochloride, methyldopa (such as Aldomet ™), and gabapentin (such

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such as Neurontin and Serada) .If a compound described in the present description is administered to a subject along with one or more other compounds known to reduce the symptoms of hormonal variation, then the effective amount of the compound described in the present description may be less than if the compound described in the present description is administered alone. Therefore, the effective amount of the compound described in the present description may be, for example, half, one third, one quarter, one sixth, or one eighth of the effective amount of the compound when administered alone.

Serotonin (5-HT) receptors comprise approximately 15 different receptors. Type 2 serotonin receptors (5-HT.sub.2) are receptors coupled to G.sub.q / G.sub.1 that mediate cellular effects by increasing cellular levels of inositol triphosphate (IP. sub.3) and diacylglycerol (DAG). According to some aspects of the present description, the serotonin receptor type 2a is the objective for the treatment or prevention of the symptoms associated with hormonal variation. The reduction of 5-HT levels increases the sensitivity of the 5-HT.sub.2A receptor in the hypothalamus, which is involved in thermoregulation. Therefore, 5-HT.sub.2A receptor modulators can be useful in the control of symptoms associated with hormonal variations.

According to the present description, dextromethorphan, for example, HBr dextromethorphan, can be used to treat the symptoms of hormonal variations. Dextromethorphan, for example, HBr dextromethorphan, is a cough suppressant drug (cough suppressant) that works by interfering with the communication between nerves in the brain. Raise the cough threshold, without inhibiting ciliary activity. However, as described in the present description, it has been unexpectedly discovered that dextromethorphan, for example, HBr dextromethorphan, is effective in reducing or eliminating the symptoms associated with hormonal variations.

According to another aspect of the present invention, dextrorphan can be used as a treatment for the symptoms of hormonal variations. Dextrorphan is the main active metabolite of dextromethorphan, for example, dextromethorphan HBr. Like dextromethorphan, for example, HBr dextromethorphan, dextrorphan can effectively treat or prevent symptoms associated with hormonal variations.

In addition, the present description describes the use of receptor antagonists that can bind to 5-HT.sub.2A and / or dopamine D.sub.2 receptors to control the symptoms associated with hormonal variations. These antagonists may include, for example, amantadine, ibogafna, ketamine, memantine, riluzole, aptiganel, dizocipline, HU-211, remacemide, ketobemidone, methadone and tramadol.

In the present description, pharmaceutical compositions for treating or preventing the symptoms of hormonal variation are also described. The pharmaceutical composition comprises an effective amount of a compound described in the present description. Also described herein is a pharmaceutical composition comprising an effective amount of a receptor antagonist for treating or preventing the symptoms of hormonal variation, wherein the receptor antagonist binds at least one receptor selected from a type 2A serotonin receptor (5-HT.sub.2A) and a type 2 dopamine receptor (D.sub.2).

The pharmaceutical composition may be a pharmaceutically acceptable form such as a dosage form.

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oral, injection, inhalation, and / or transdermal patch. The oral dosage forms may be, for example, a controlled release dosage form, a rapidly dispersed dosage form with a porous network of a matrix composition, or a solid dosage form that rapidly disintegrates. For example, an oral dosage form may be composed of a microparticle composition and a biodegradable microparticle polymer carrier and with acceptable biocompatibility. An oral dosage form may include at least one sustained release microparticle produced by dissolving in a solvent with a biodegradable and biocompatible polymer to form an organic phase, and extracting the solvent to form microparticles. Another oral dosage form may be a microencapsulated pharmaceutical composition having a selected release profile prepared by a method for preparing microparticles.

The method for preparing microparticles may involve: (a) preparing an emulsion having a first phase and a second phase, wherein the first phase includes the active agent, a polymer, and a solvent for the polymer; (b) cooling the emulsion in a cooling liquid to form microparticles containing the active agent; (c) select an intermediate drying degree of the microparticles to be carried out so that the selected release profile is achieved; (d) wash the microparticles; and (e) perform the final drying of the microparticles.

The oral dosage form may be a multi-phase sustained release microparticle composition, prepared by a process that involves: dissolving in an solvent the active agents and a biodegradable and biocompatible polymer to form an organic phase; extract the solvent to form microparticles; and combining the microparticles that have a plurality of sizes to thereby form a composition that supplies the active agent in a multiphasic manner.

A pharmaceutical composition optionally includes the active agents and at least one substance selected from pharmaceutically acceptable carriers, nutrients, vitamins, other active ingredients, sweeteners, flavoring agents, coloring agents, surfactants, preservatives, antioxidants, viscosity enhancers, and minerals. As used herein, "pharmaceutically acceptable" is intended to include ingredients that are biologically tolerable. As used herein, "biologically tolerable" refers to substances that are not toxic to humans. The use of such ingredients is well known in the art and, therefore, it is not necessary to discuss in the present description the examples and additional methods for incorporating each of the compositions at effective levels. As used herein, "pharmaceutically acceptable carrier" refers to solvents, binders, disintegrating agents, lubricants, excipients, absorption delay agents, and the like.

In addition, in the present description cases are described for carrying out a method of the invention. Typically, the cases described in the present description comprise a compound used in the present description and the instructions on how to perform at least one method described in the present description. The compound is generally supplied in the kits in an amount sufficient to treat at least one patient at least once to reduce, eliminate, or prevent the symptoms of hormonal variations. Alternatively, the kit may comprise a dose of the compound wherein the dose is not sufficient to be effective for the reduction, elimination, or prevention of the symptoms of hormonal variations by itself, but when administered with another dose at a later time. , becomes effective. The compound supplied in the cases can be supplied as a solution, gel, tablet, capsule, powder, injection, suppository, infusible, pill, cream, ointment, inhalant, transdermal patch, and the like. The kits may also comprise some or all of the other reagents and supplies necessary to perform at least one embodiment of a method described in the present description.

In its simplest form, a case described in the present description comprises a container containing at least one type of compound or at least one composition described in the present description. Therefore, in aspects, the case described in the present description comprises a container containing at least one type of compound or a composition comprising a compound. In other aspects, the case comprises multiple containers, each of which may contain at least one compound, compositions comprising the compound, or other substances that are useful for performing one or more aspects described in the present description.

The container may be of any material suitable for containing a composition of the invention or other substance useful for performing a method described in the present description. Therefore, the container can be a vial or a blister. This can be made of any suitable material, such as glass, plastic, metal, or paper or a paper product. In aspects, it is a blister or a glass or plastic bottle that can be sealed, such as with a cap, a cap and seal crimped, or a plastic or metal lid. In aspects, the container comprises an effective amount of the compound to reduce, eliminate, or prevent the symptoms of hormonal variation. One skilled in the art can select the amount of compound contained in the container without undue experimentation based on numerous parameters that are relevant in accordance with the present description.

In aspects, the container is provided as a component of a larger unit that typically comprises packaging materials (referred to below as a case for simplicity purposes). The case described in the present description may include a suitable container and instructions and / or other information related to the use of the compositions. Typically, the case is made of a resistant material, such as

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cardboard and plastic, and may contain instructions or other information printed directly on it. The case may comprise multiple containers containing the composition described in the present description. In such cases, each container may be of the same size, and contain the same amount of composition, as each of the other containers, or different containers may have different sizes and / or contain different amounts of compositions or compositions having different constituents. One skilled in the art will immediately appreciate that this description provides for numerous configurations of different sizes and contents of containers and, therefore, it is not necessary to mention specifically all the permutations in the present description.

In general, the case comprises containers for containing the components of the case, and is considered a single package comprising a combination of containers. Therefore, it is said that the components are in a combination of containers inside the case. In addition to a container containing a composition described in the present description, the case may comprise additional containers containing additional compositions described in the present description. Each container can contain enough compound for a single dose of one aspect of the method described in the present description, or it can contain enough for two or more doses. The various containers may contain different amounts of the composition described in the present description. Therefore, in aspects, the case comprises a sufficient amount of compound to perform an aspect of the method described in the present description. The kit may also comprise some or all of the supplies and materials necessary to prepare and perform a method described in the present description, such as, but not limited to, syringes, sterile water or a sterile aqueous solution. In some embodiments, the cases comprise one or more liquids to hydrate the compositions of the cases.

EXAMPLES

The following examples are provided to illustrate that embodiments of the present invention may reduce symptoms of hormonal variations, including hot flashes, night sweats, and blood pressure fluctuations. The embodiments of the invention are effective for patients under various conditions. However, one skilled in the art will appreciate that these examples are for purposes of illustration.

Example 1: Dextromethorphan, for example, HBr dextromethorphan resolved hot flashes in a case involving partial hysterectomy, hormone replacement therapy, and breast cancer surgery / treatment

As noted above, embodiments of the invention involve administering a therapeutically effective amount of (dextromethorphan, for example, dextromethorphan HBr or dextrorphan) to alleviate the symptoms associated with hormonal variations. This example involves the use of HBx dextromethorphan which has been used in a patient with a history of breast cancer to successfully relieve the incidence of hot flashes or other symptoms of hormonal variations. A real specific past example of the use of the methods and compositions of the invention with a patient is described below, which illustrates the efficacy of dextromethorphan, for example, HBr dextromethorphan for the relief of symptoms associated with hormonal variations. The following example of a patient illustrates the efficacy of dextromethorphan, for example, HBr dextromethorphan for the relief of symptoms associated with hormonal variations. One skilled in the art will appreciate that this specific example is not intended to limit the scope of the present description. For example, aspects described in the present description may use other regimens, including 5-HT.sub.2A and / or dopamine D.sub.2 receptor antagonists.

In September 1993, a 31-year-old woman who had experienced severe menstrual cycles needed a partial hysterectomy. A few months after surgery, he began to experience hot flashes, night sweats and insomnia. These incidents took place several times a day / night with a duration of a few minutes. Approximately one year after surgery, Cenestin ™ (a type of hormone replacement therapy, that is, "HRT") was given. After starting with Cenestin ™, the patient reported that the frequency and intensity of her hot flashes were reduced. In 2006, Cenestin ™ was discontinued due to an increase in hot flashes, night sweats and irritability.

At that time, the patient began consuming doses of Wellbutrin ™ and receiving another estrogen and testosterone hormone replacement therapy to treat hot flashes, night sweats and other menopausal symptoms. After starting this new therapy, the patient reported that the frequency and intensity of her hot flashes, night sweats and other menopausal symptoms were markedly reduced.

In November 2008, at the age of 46, the patient was diagnosed with stage 2 breast cancer and HRT was immediately suspended. Subsequently, the patient underwent a lumpectomy and the removal of fourteen lymph nodes (one tested positive). At this time, menopausal symptoms returned.

In December 2008, the patient underwent an intense chemotherapy treatment that lasted until April 2009. At this time, she continued with a less intense chemotherapy treatment until November 2009. The patient also received radiation therapy since April 2009. until June 2009. At the end of radiation therapy, the

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Four. Five

patient started a Tamoxifen ™ regimen. From the beginning of treatment with Tamoxifen ™, hot flashes, night sweats and other menopausal symptoms increased in intensity.

In February 2009, the patient was treated with Vitamin E and Clonidine ™, a blood pressure medication that has also been used to reduce menopausal symptoms. Clonidine ™ is a direct-acting a2 adrenergic agonist that is used to treat various medical conditions. Clonidine ™ had no impact on the reduction of menopausal symptoms. Both Clonidine ™ and Wellbutrin ™ were suspended in June 2009.

In June 2009, the patient was treated with Neurontin ™ (generic name gabapentin), a medicine for seizures or nerve pain that has also been used to reduce menopausal symptoms. It was originally developed for the treatment of epilepsy and, currently, gabapentin is widely used to relieve pain, especially neuropathic pain. Neurontin ™ had no impact on the reduction of menopausal symptoms and was discontinued in August 2009. At this time, the patient was treated with Effexor ™ (generic name venlafaxine), a medication used primarily for the treatment of depression. major, generalized anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, and menopausal hot flashes in adults. Effexor ™ had no impact on the reduction of menopausal symptoms and was discontinued in October 2009.

At that time, the patient started again with Wellbutrin ™ to treat hot flashes, night sweats and other menopausal symptoms. Wellbutrin ™ had no impact on the reduction of hot flashes, night sweats and other menopausal symptoms. Also, at this time, it started with black cohosh (an herbal remedy) to treat the indications, which had no impact on the reduction of the indications.

Then he started with dextromethorphan, for example, dextromethorphan HBr in January 2010 at a dose of 30 mg per day (15 mg every 12 hours), and the patient reported that the incidence of hot flashes, night sweats and other menopausal symptoms was reduced significantly two days after starting with dextromethorphan, for example, dextromethorphan HBr. After three days, hot flashes, night sweats and other menopausal symptoms were drastically reduced and disappeared completely on the third day. The dosage continued and remained the same for another 5 days.

Then, with the patient's authorization, dextromethorphan, for example, HBr dextromethorphan was discontinued and menopausal symptoms reappeared within 24 hours. Symptoms were removed again within 24 hours after starting treatment with dextromethorphan again, for example, dextromethorphan HBr. While continuing treatment with dextromethorphan, for example, HBr dextromethorphan and with the patient's authorization, Wellbutrin ™ was discontinued and hot flashes, night sweats and menopausal smithomas did not reappear.

Example 2: Dextromethorphan, for example, HBr dextromethorphan resolved hot flashes in menopausal women with no history of breast cancer

The following Table summarizes the data of female test subjects who had not had a history of breast cancer but who experienced symptoms of hormonal variation probably due to their entry into natural menopause. The dose administered in these test cases was 15 mg in the morning and 15 mg at night dextromethorphan, for example, dextromethorphan HBr. The decrease in symptoms of hormonal variation was observed by assessing the severity and frequency of hot flashes.

5

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Four. Five

fifty

55

60

65

Table 1. Dextromethorphan response, for example, HBr dextromethorphan in menopausal women with no history of breast cancer

 Test subject

 Age Number of years with hot flashes Frequency of hot flashes Other health problems Other treatments previously used without response Response to Dex.HBr

 one

 48 6 4 times / day High blood pressure Hormonal patch, Black Cohosh No more hot flashes

 3 times / night

 2

 61 5-7 3-4 times / day, about 2 times / night Partial hysterectomy 25 years ago Hormonal patch, Flashease, Amberen, Black Cohosh No more hot flashes

 3

 51 Several None Moderate response (some reduction of hot flashes)

 4

 50 Several None No more hot flashes

 5

 54 3-4 There are no major health problems No more hot flashes

As can be seen in Table 1, the administration of dextromethorphan, for example, HBr dextromethorphan to five women without any history of breast cancer, but with symptoms of hormonal variation, relieves the symptoms as seen by a reduction of hot flashes. In fact, four of the five women no longer had hot flashes with the drug.

Example 3: Standard protocol to resolve the symptoms of hormonal variation

The following example provides a protocol for the administration of a compound to reduce, eliminate, or prevent the symptoms of hormonal variation. Although dextromethorphan, for example, HBr dextromethorphan is specifically used in this protocol, receptor antagonists, wherein the receptor antagonist binds to at least one selected from a serotonin receptor type 2A (5-HT.sub. 2A) and a type 2 dopamine receptor (D.sub.2), can be used in the methods and compositions described in the present description.

Protocol:

Identify a subject that has one or more symptoms of hormonal variation;

Administer to the subject an initial dose of 15 mg dextromethorphan, for example, dextromethorphan HBr in the morning and at night for a total dose of 30 mg dextromethorphan, for example, dextromethorphan HBr;

Monitor the symptoms of hormonal variation, such as hot flashes.

If the symptoms are maintained or reduced, an additional dose of 15 mg dextromethorphan, for example, dextromethorphan HBr may be administered in the afternoon to try to eliminate the symptoms. Alternatively, the amount of dextromethorphan, for example, dextromethorphan HBr can be increased in the morning and at night. As is usual practice in the medical field, it may be necessary to adjust the dose of compounds administered to each subject depending on the subject's age, weight, gender, metabolism, etc.

If the symptoms are eliminated with the use of the protocol described above, the dose of dextromethorphan, for example, dextromethorphan HBr can be maintained or the dose can be reduced to find the minimum dose that still eliminates the symptoms of the subject.

Example 4: Standard protocol that includes administration together with gabapentin to resolve the symptoms of hormonal variation

5

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fifteen

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The compounds described in the present description can also administer a subject together with other compounds known to reduce, eliminate, or prevent hormonal variations. The following example provides a protocol for the administration of dextromethorphan, for example, HBr dextromethorphan, together with gabapentin, a compound that has been shown to reduce hot flashes in clinical trials. As discussed in the previous Example, although dextromethorphan, for example, HBr dextromethorphan is specifically used in this protocol, receptor antagonists, wherein the receptor antagonist binds at least one selected from a serotonin receptor of the type 2A (5-HT.sub.2A) and a type 2 dopamine receptor (D.sub.2), can be used in the methods and compositions described in the present description.

Protocol:

Identify a subject that has one or more symptoms of hormonal variations;

Administer to the subject an initial dose of 15 mg dextromethorphan, for example, dextromethorphan HBr and 300 mg of gabapentin in the morning and at night for a total dose of 30 mg dextromethorphan, for example, dextromethorphan HBr and 600 mg of gabapentin per dfa;

Monitor the symptoms of hormonal variation, such as hot flashes.

If the symptoms are maintained or reduced, an additional dose of 15 mg of dextromethorphan, for example, dextromethorphan HBr and 300 mg of gabapentin may be administered in the afternoon to try to eliminate the symptoms. Alternatively, the amounts of dextromethorphan, for example, dextromethorphan HBr and / or gabapentin can be increased in the morning and at night.

If the symptoms are eliminated with the use of the protocol described above, the dose of dextromethorphan, for example, dextromethorphan HBr and gabapentin can be maintained or reduced. For example, the subject may try to take a single dose per day. As another example, the subject may choose to reduce the amount of each compound administered in the morning and at night. As examples, the amount of gabapentin can be reduced to a lower level, such as 400 mg per day, 300 mg per day, 200 mg per day, 100 mg per day, 50 mg per day or even as low as 1 mg per day. .

Claims (13)

5 10 fifteen twenty 25 30 35 40 Four. Five fifty 55 60 1. Dextromethorphan or dextrorphan, or a pharmaceutically acceptable salt of any of these, for use in a method for the treatment or prevention of symptoms of hormonal variation; said method comprises identifying a subject that has one or more symptoms of hormonal variations selected from hot flashes and night sweats and administering an effective amount of said dextromethorphan or dextrorphane or salt to the subject. 2. Dextromethorphan or dextrorphan or a pharmaceutically acceptable salt of any of these for use according to claim 1, wherein said dextromethorphan or dextrorphan or pharmaceutically acceptable salt is administered (i) in a controlled release dosage form or one of sustained release; or (ii) through a transdermal patch. 3. Dextromethorphan or dextrorphan, or a pharmaceutically acceptable salt of any of these, in combination with another compound known to reduce or prevent the symptoms of hormonal variation, for use in a method for the treatment or prevention of symptoms of hormonal variation selected from hot flashes and night sweats; said method comprises identifying a subject that has one or more symptoms of hormonal variations and administering an effective amount of said dextromethorphan or dextrorphan or salt and said other compound to the subject. 4. Dextromethorphan or dextrorphan or a pharmaceutically acceptable salt of any of these for use according to claim 3, wherein the other compound known to reduce or prevent the symptoms of hormonal variation is selected from the group consisting of a conjugated estrogen, bupropian, venlafaxine, fluoxetine, duloxetine, sertraline, clonidine, clonidine hydrochloride, methyldopa, and gabapentin. 5. Dextromethorphan or dextrorphan or a pharmaceutically acceptable salt of any of these for use according to claim 4, wherein said other compound is gabapentin. 6. Dextromethorphan or dextrorphan or a pharmaceutically acceptable salt of any of these for use according to claim 5, wherein the amount of dextromethorphan or dextrorphan administered is from 0.1 to 120 mg per day and the amount of gabapentin administered is from 1 mg to 900 mg per day. 7. Dextromethorphan or dextrorphan or a pharmaceutically acceptable salt of any of these for use according to claim 6, wherein said dextromethorphan or dextrorphan or pharmaceutically acceptable salt and said other known compound to reduce or prevent the symptoms of hormonal variation are administer: (i) in a controlled release or sustained release dosage form; or (ii) through a transdermal patch. 8. Dextromethorphan or dextrorphan or a pharmaceutically acceptable salt of any of these for use according to any of the preceding claims, wherein said salt is dextromethorphanHBr. 9. Dextromethorphan or dextrorphan or a pharmaceutically acceptable salt of any of these for use according to any of the preceding claims, wherein the effective amount of dextromethorphan or dextrorphan is from 0.1 to 120 mg per day. 10. Dextromethorphan or dextrorphan or a pharmaceutically acceptable salt of any of these for use according to any of the preceding claims, wherein the subject is (i) a female; or (ii) a man. 11. Use of dextromethorphan or dextrorphan, or a pharmaceutically acceptable salt of any of these, for the manufacture of a pharmaceutical composition for the treatment or prevention of hormonal variation symptoms selected from hot flashes and night sweats, wherein said dextromethorphan or dextrorphan or salt is present in said pharmaceutical composition in an effective amount in a pharmaceutically acceptable carrier. 12. Use according to claim 11, wherein the salt is dextromethorphanHBr. 13. Use according to claim 11 or 12, wherein said dextromethorphan or dextrorphan or pharmaceutically acceptable salt thereof is administered (i) in a controlled release or sustained release dosage form; or (ii) through a transdermal patch.